Research Center sarrollo Of Medicamentos

Havana, Cuba

Research Center sarrollo Of Medicamentos

Havana, Cuba
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de la Vega-Hernandez K.,University of Habana | Antuch M.,University of Habana | Cuesta-Rubio O.,Technical University of Machala | Nunez-Figueredo Y.,Research Center sarrollo Of Medicamentos | Pardo-Andreu G.L.,University of Habana
Journal of Inorganic Biochemistry | Year: 2017

Oxidative stress resulting from iron and reactive oxygen species (ROS) homeostasis breakdown has been implicated in several diseases. Therefore, molecules capable of binding iron and/or scavenging ROS may be reasonable strategies for protecting cells. Rapanone is a naturally occurring hydroxyl-benzoquinone with a privileged chelating structure. In this work, we addressed the antioxidant properties of rapanone concerning its iron-chelating and scavenging activities, and its protective potential against iron and tert-butyl hydroperoxide-induced damage to mitochondria. Experimental determinations revealed the formation of rapanone-Fe(II)/Fe(III) complexes. Additionally, the electrochemical assays indicated that rapanone oxidized Fe(II) and O2−[rad], thus inhibiting Fenton-Haber-Weiss reactions. Furthermore, rapanone displayed an increased 2,2-diphenyl-1-picrylhydrazyl radical scavenging ability in the presence of Fe(II). The above results explained the capacity of rapanone to provide near-full protection against iron and tert-butyl hydroperoxide induced mitochondrial lipid peroxidation in energized organelles, which fail under non-energized condition. We postulate that rapanone affords protection against iron and reactive oxygen species by means of both iron chelating and iron-stimulated free radical scavenging activity. © 2017 Elsevier Inc.


Delgado R.,Research Center sarrollo Of Medicamentos | Garrido G.,Católica del Norte University
Cell Proliferation | Year: 2014

Objectives: Mangifera indica L. (mango) stem bark aqueous extract (MSBE) that has antioxidant, anti-inflammatory and immunomodulatory properties, can be obtained in Cuba. It is rich in polyphenols, where mangiferin is the main component. In this study, we have tested DNA damage and protection effects of MSBE and mangiferin on primary human lymphocytes and lymphoblastoid cells. Material and methods: Cell suspensions were incubated with the products (50-1000 μg/ml) for experiments on damage induction, and evaluation of any potential protective effects (5-100 μg/ml) for 60 min at 37 °C. Irradiation was performed using a γ-ray source, absorbed dose 5 Gy. At the end of exposure, DNA damage, protection and repair processes were evaluated using the comet assay. Results: MSBE (100-1000 μg/ml) induced DNA damage in a concentration dependent manner in both cell types tested, primary cells being more sensitive. Mangiferin (200 μg/ml) only induced light DNA damage at higher concentrations. DNA repair capacity was not affected after MSBE or mangiferin exposure. On the other hand, MSBE (25 and 50 μg/ml) and mangiferin (5-25 ug/ml) protected against gamma radiation-induced DNA damage. Conclusions: These results show MSBE has protector or harmful effects on DNA in vitro depending on the experimental conditions, which suggest that the extract could be acting as an antioxidant or pro-oxidant product. Mangiferin was involved in protective effects of the extract. © 2013 John Wiley & Sons Ltd.


Garrido-Suarez B.B.,Research Center sarrollo Of Medicamentos | Garrido G.,Católica del Norte University | Castro-Labrada M.,Research Center sarrollo Of Medicamentos | Merino N.,Research Center sarrollo Of Medicamentos | And 4 more authors.
Pharmacology Biochemistry and Behavior | Year: 2014

The present study examines the possible effect of the glucosylxanthone mangiferin (MG) on pain-related behaviors in a tonic acute pain model (formalin test at 5%) and in a chronic constriction injury (CCI) model to clarify the underlying transient and long-term mechanisms. Acute administration of MG (10-100 mg/kg, i.p.) reduced licking/biting exclusivity in the tonic phase of formalin test in a naloxone and yohimbine-sensitive manner. This effect was enhanced by a nonselective nitric oxide synthase (NOS) inhibitor (NG-monomethyl-l-arginine) and by a non-competitive N-methyl-d-aspartate (NMDA) antagonist (ketamine), but it was reversed by the NOS substrate (l-arginine). Pre-treatment with intrathecal yohimbine prevented the anti-hypernociceptive effect of systemic MG. Pre-treatment during 4 days before surgical and 3 days after CCI with MG (50 mg/kg, i.p.) reduced mechanical hypernociception and decreased the signs of Wallerian degeneration (WD) of the sciatic nerve. MG improved the PC-12 cellular viability exposure to glutamate-mediated neuronal death, also involved in neuropathic pain. The findings of this study suggest that MG shows ability to decrease tonic pain in the formalin test. A transient activity of this xanthone on nociceptive pathways mediated by α2 adrenergic receptors in cooperation with the opioid system could be involved, at least in part, in this effect. Its neuroprotective effect by preventing WD in mononeuropathic rats could be implicated in the mechano-antihypernociceptive long term mechanisms. © 2014 Elsevier Inc.


Nunez-Figueredo Y.,Research Center sarrollo Of Medicamentos | Ramirez-Sanchez J.,Research Center sarrollo Of Medicamentos | Delgado-Hernandez R.,Research Center sarrollo Of Medicamentos | Porto-Verdecia M.,Research Center sarrollo Of Medicamentos | And 9 more authors.
European Journal of Pharmacology | Year: 2014

The ischemic stroke cascade is composed of several pathophysiological events, providing multiple targets for pharmacological intervention. JM-20 (3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro-1H-pyrido[2,3-b][1,5] benzodiazepine) is a novel hybrid molecule, in which a benzodiazepine portion is covalently linked to a dihydropyridine ring, forming a new chemical entity with potential multisite neuroprotective activity. In the present study, JM-20 prevented PC-12 cell death induced either by glutamate, hydrogen peroxide or KCN-mediated chemical hypoxia. This molecule also protected cerebellar granule neurons from glutamate or glutamate plus pentylenetetrazole-induced damage at very low micromolar concentrations. In rat liver mitochondria, JM-20, at low micromolar concentrations, prevented the Ca2+-induced mitochondrial permeability transition, as assessed by mitochondrial swelling, membrane potential dissipation and organelle release of the pro-apoptotic protein cytochrome c. JM-20 also inhibited the mitochondrial hydrolytic activity of F1F0-ATP synthase and Ca2+ influx. Therefore, JM-20 may be a multi-target neuroprotective agent, promoting reductions in neuronal excitotoxic injury and the protection of the mitochondria from Ca 2+-induced impairment as well as the preservation of cellular energy balance. © 2014 Elsevier B.V.


Nunez-Figueredo Y.,Research Center sarrollo Of Medicamentos | Ramirez-Sanchez J.,Research Center sarrollo Of Medicamentos | Hansel G.,Federal University of Rio Grande do Sul | Simoes Pires E.N.,Federal University of Rio Grande do Sul | And 10 more authors.
Neuropharmacology | Year: 2014

We previously showed that JM-20, a novel 1,5-benzodiazepine fused to a dihydropyridine moiety, possessed an anxiolytic profile similar to diazepam and strong neuroprotective activity in different cell models relevant to cerebral ischemia. Here, we investigated whether JM-20 protects against ischemic neuronal damage in vitro and in vivo. The effects of JM-20 were evaluated on hippocampal slices subjected to oxygen and glucose deprivation (OGD). For in vivo studies, Wistar rats were subjected 90 min of middle cerebral artery occlusion (MCAo) and oral administration of JM-20 at 2, 4 and 8 mg/kg 1 h following reperfusion. Twenty-four hours after cerebral blood flow restoration, neurological deficits were scored, and the infarct volume, histopathological changes in cortex, number of hippocampal and striatal neurons, and glutamate/aspartate concentrations in the cerebrospinal fluid were measured. Susceptibility to brain mitochondrial swelling, membrane potential dissipation, H2O2 generation, cytochrome c release, Ca2+ accumulation, and morphological changes in the organelles were assessed 24 h post-ischemia. In vitro, JM-20 (1 and 10 μM) administered during reperfusion significantly reduced cell death in hippocampal slices subjected to OGD. In vivo, JM-20 treatment (4 and 8 mg/kg) significantly decreased neurological deficit scores, edema formation, total infarct volumes and histological alterations in different brain regions. JM-20 treatment also protected brain mitochondria from ischemic damage, most likely by preventing Ca2+ accumulation in organelles. Moreover, an 8-mg/kg JM-20 dose reduced glutamate and aspartate concentrations in cerebrospinal fluid and the deleterious effects of MCAo even when delivered 8 h after blood flow restoration. These results suggest that in rats, JM-20 is a robust neuroprotective agent against ischemia/reperfusion injury with a wide therapeutic window. Our findings support the further examination of potential clinical JM-20 use to treat acute ischemic stroke. © 2014 Elsevier Ltd. All rights reserved.


Nunez-Figueredo Y.,Research Center sarrollo Of Medicamentos | Pardo-Andreu G.L.,University of Habana | Ramirez-Sanchez J.,Research Center sarrollo Of Medicamentos | Delgado-Hernandez R.,Research Center sarrollo Of Medicamentos | And 6 more authors.
Brain Research Bulletin | Year: 2014

Because mitochondrial oxidative stress and impairment are important mediators of neuronal damage in neurodegenerative diseases and in brain ischemia/reperfusion, in the present study, we evaluated the antioxidant and mitoprotective effect of a new promising neuroprotective molecule, JM-20, in mitochondria and synaptosomes isolated from rat brains. JM-20 inhibited succinate-mediated H2O2 generation in both mitochondria and synaptosomes incubated in depolarized (high K+) medium at extremely low micromolar concentration and with identical IC50 values of 0.91μM. JM-20 also repressed glucose-induced H2O2 generation stimulated by rotenone or by antimycin A in synaptosomes incubated in high sodium-polarized medium at extremely low IC50 values of 0.395μM and 2.452μM, respectively. JM-20 was unable to react directly with H2O2 or with superoxide anion radicals but displayed a cathodic reduction peak at -0.71V, which is close to that of oxygen (-0.8V), indicating high electron affinity. JM-20 also inhibited uncoupled respiration in mitochondria or synaptosomes and was a more effective inhibitor in the presence of the respiratory substrates glutamate/malate than in the presence of succinate. JM-20 also prevented Ca2+-induced mitochondrial permeability transition pore opening, membrane potential dissipation and cytochrome c release, which are key pathogenic events during stroke. This molecule also prevented Ca2+ influx into synaptosomes and mitochondria; the former effect was a consequence of the latter because JM-20 inhibition followed the patterns of carbonyl cyanide p-trifluoromethoxyphenyl hydrazone (FCCP), which is a classic mitochondrial uncoupler. Because the mitochondrion is considered an important source and target of neuronal cell death signaling after an ischemic insult, the antioxidant and protective effects of JM-20 against the deleterious effects of Ca2+ observed at the mitochondrial level in this study may endow this molecule with the ability to succeed in mitochondrion-targeted strategies to combat ischemic brain damage. © 2014 Elsevier Inc..


Garrido-Suarez B.B.,Research Center sarrollo Of Medicamentos | Garrido G.,Católica del Norte University | Garcia M.E.,Research Center sarrollo Of Medicamentos | Delgado-Hernandez R.,Research Center sarrollo Of Medicamentos
Phytotherapy Research | Year: 2014

This study aimed to assess the effects of a Mangifera indica stem bark extract (MSBE) and mangiferin (MG) on pain-related acute behaviors in the formalin 5% test. Rats received repeated oral MSBE (125-500 mg/kg) once daily for 7 days before formalin injection. Other four groups with the same treatments were performed in order to study the effect of MSBE on the formalin-induced long-term secondary mechano-hyperalgesia at 7 days after the injury by means of the pin-prick method. Additional groups received a single oral MSBE dose (250 mg/kg) plus ascorbic acid (1 mg/kg, i.p.). Also, repeated oral MG doses (12.5-50 mg/kg) during 7 days were administered. MSBE decreased licking/biting and flinching behaviors only in phase II and reduced the long-term formalin injury-induced secondary chronic mechano-hyperalgesia. The combination of MSBE plus ascorbic acid produced a reinforcement of this effect for flinching behavior, advising that antioxidant mechanisms are involved, at least in part, in these actions. Chronic administration of MG reproduced the effects of MSBE. For the first time, the antihyperalgesic effects of MSBE and MG in formalin 5% test, a recommended concentration for studying the antinociceptive activity of nitric oxide-related and N-methyl-D-aspartate-related compounds, were reported. These results could represent an important contribution to explain the analgesic ethnobotanical effects recognized to M. indica and other species containing MG. Copyright © 2014 John Wiley & Sons, Ltd.


Garrido-Suarez B.,Research Center sarrollo Of Medicamentos | Garrido-Suarez B.,Clinica Del Dolor Hospital Docente Clinico Quirurgico 10 Of Octubre | Garrido G.,Católica del Norte University | Delgado R.,Research Center sarrollo Of Medicamentos | And 2 more authors.
Forschende Komplementarmedizin | Year: 2011

Background: Neuroimmune activation has been proposed as a source of new targets for therapeutic intervention in neuropathic pain. Vimang® is an aqueous extract from Mangifera indica L. (common mango) that is traditionally used in Cuba for its antioxidant, anti-inflammatory, analgesic, and immunomodulatory properties. In the present case report, we determine its potential effects in patients with zoster-associated pain. Patients and Methods: 12 patients with zoster-associated pain (6 with subacute herpetic neuralgia and 6 with post-herpetic neuralgia) received a daily dose of 1,800 mg of extract (2 coated 300 mg tablets, 3 times daily before meals) together with low doses of amitriptyline (10-25 mg/day) for 120 days. In addition to the tablets, patients used Vimang® cream 1.2% as a topical agent. The average daily pain score using the Likert scale, area and rate of dynamic allodynia, rate of thermal allodynia, and frequency of burning spontaneous pain were evaluated. Results: Pain scores and sensory abnormalities decreased significantly (p < 0.05) with respect to baseline data from week 4. No adverse events were reported. Conclusion: These results suggest that Vimang® could be beneficial in the treatment of neuropathic pain. However, a controlled clinical trial is necessary to confirm this hypothesis. Copyright © 2011 S. Karger AG, Basel.


PubMed | Research Center sarrollo Of Medicamentos, University of Habana and Federal University of Rio Grande do Sul
Type: | Journal: Neurochemistry international | Year: 2015

Cerebral ischemia is the third most common cause of death and a major cause of disability worldwide. Beyond a shortage of essential metabolites, ischemia triggers many interconnected pathophysiological events, including excitotoxicity, oxidative stress, inflammation and apoptosis. Here, we investigated the neuroprotective mechanisms of JM-20, a novel synthetic molecule, focusing on the phosphoinositide-3-kinase (PI3K)/Akt survival pathway and glial cell response as potential targets of JM-20. For this purpose, we used organotypic hippocampal slice cultures exposed to oxygen-glucose deprivation (OGD) to achieve ischemic/reperfusion damage invitro. Treatment with JM-20at 0.1 and 10M reduced PI incorporation (indicative of cell death) after OGD. OGD decreased the phosphorylation of Akt (pro-survival) and GSK 3 (pro-apoptotic), resulting in respective inhibition and activation of these proteins. Treatment with JM20 prevented the reduced phosphorylation of these proteins after OGD, representing a shift from pro-apoptotic to pro-survival signaling. The OGD-induced activation of caspase-3 was also attenuated by JM-20 treatment at 10M. Moreover, in cultures treated with JM-20 and exposed to OGD conditioning, we observed a decrease in activated microglia, as well as a decrease in interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)- release into the culture medium, while the level of the anti-inflammatory IL-10 increased. GFAP immunostaining and IB4 labeling showed that JM-20 treatment significantly augmented GFAP immunoreactivity after OGD, when compared with cultures exposed to OGD only, suggesting the activation of astroglial cells. Our results confirm that JM-20 has a strong neuroprotective effect against ischemic injury and suggest that the mechanisms involved in this effect may include the modulation of reactive astrogliosis, as well as neuroinflammation and the anti-apoptotic cell signaling pathway.


Figueredo Y.N.,Research Center sarrollo Of Medicamentos | Rodriguez E.O.,University of Habana | Reyes Y.V.,University of Habana | Dominguez C.C.,Research Center sarrollo Of Medicamentos | And 5 more authors.
Neurological Research | Year: 2013

Objectives: The aim of this study was to investigate the effects of oral administration of a novel benzodiazepine derivative, JM-20, on the neurological behavior of different rodent models, focusing on the GABAergic effect. We have also investigated the acute toxicity of oral administration of JM-20 in mice. Methods: Mice or rats received oral administration of JM-20 at 2, 4, 8, and 10 mg/kg to evaluate the sedative/hypnotic, anxiolytic, and anticonvulsant effects, as well as the influence on the stereotyped behavior induced by amphetamine. Diazepam (DZP) was used as a positive control. In addition, the mice received a single oral JM-20 dose of 2000 mg/kg to evaluate the acute toxicity. Results: In a dose-dependent manner, JM-20 (i) increased the number of crossings and decreased the number of rearings in the open-field test; (ii) decreased the aggressive behavior of socially-isolated mice; and (iii) increased the latency period for tonic seizure's onset and the percentage of survival of animals with seizures. Moreover, JM-20 increased the sleeping time induced by barbiturates and the time spent and the number of entries in the open arms of the elevated plus-maze test. In the JM-20 toxicity test, no mortality was observed and only minor signs of toxicity associated with sedation were detected. Conclusions: These results indicate that JM-20 has an anxiolytic profile similar to DZP and its dihydropyridine moiety did not appear to interfere with the GABAergic activity associated with benzodiazepine. Furthermore, JM-20 did not show significant acute toxic effects in mice. © W. S. Maney & Son Ltd 2013.

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